Recent evidence suggests that, in addition to analgesia, opioids produce unexpected, paradoxical pain in both preclinical and clinical settings. In the case of morphine, opioid-induced pain limits not only acute antinociceptive efficacy but also appears to promote the decreased antinociception seen with sustained exposure (i.e., behavioral opioid antinociceptive tolerance). Manipulations which block morphine-induced pain also block the decrease in antinociceptive potency seen with sustained morphine, suggesting that opioid-induced pain may represent an important component of antinociceptive tolerance to this drug. Among the manipulations which block morphine-induced pain and antinociceptive tolerance are rostral ventromedial medulla (RVM) injection of lidocaine and bilateral lesions of the dorsolateral funiculus (DLF) suggesting a tonically active descending pain modulatory (facilitatory) system which maintains morphine-induced pain and antinociceptive tolerance. Whether the observations made with morphine extend to other agonists of differing opioid receptor selectivity is not known. This proposal hypothesizes that morphine enhances cholecystokinin (CCK) release in the RVM which then promotes opioid-induced pain and antinociceptive "tolerance." Supporting this possibility are preliminary data which show that RVM CCK produces "pain" in animals not exposed to opioids which is blocked by DLF lesions. Additionally, acute and sustained morphine increases release of CCK-LI in the RVM. Three aims will test this hypothesis. Aim 1 will investigate the release of CCK-LI in the RVM following acute local or systemic morphine, the time-course of this effect and the opioid receptor mediating this effect. Aim 2 will address the actions of sustained systemic morphine in regulating enhanced RVM CCK-LI release, its time-course and correlation to pain, and the opioid receptor mediating enhancement of RVM CCK-LI release during sustained opioid delivery. Aim 3 determines if an RVM CCK antagonist prevents the development of opioid induced pain and prevents or reverses spinal or systemic opioid antinociceptive tolerance. These studies will determine if opioid-induced release of RVM CCK represents the tonic driving force which maintains morphine- or opioid-induced pain and antinociceptive tolerance. The studies offer new insights into physiological mechanisms of opioid tolerance and strategies which might be employed to prevent opioid-induced pain and antinociceptive tolerance. These approaches may allow for sustained efficacy of morphine or opioids and their use in the treatment of chronic or prolonged pain states.